The prevalence of antibiotic resistance in bacteria is becoming one of the leading public health threats. Current antibiotics interfere with the critical biological processes of the pathogens and cause death or growth arrest of the bacteria. As a result, antibiotic therapy exerts a strong selective pressure to favor emergence of antibiotic resistant strains. In order to circumvent this serious problem, alternative antimicrobial reagents are needed that suppress the virulence of the pathogens without generating strong selection for antibiotic resistance.
Bacteria can develop biofilm on a submerged surface. Bacteria in biofilm behave differently from planktonic bacteria, especially in term of their response to antibiotic treatment (Donlan, 2001. Emerg. Infect. Dis. 7:277-281). Biofilm formation on or within indwelling medical devices such as catheters, mechanical heart valves, pacemakers, prosthetic joints, and contact lenses pose a critical problem for medical care. Both gram-negative and gram-positive bacteria can form biofilms on indwelling medical devices. The most common biofilm-forming bacteria include Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus viridans, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa (Donlan, 2001, supra).
Among these biofilm-forming bacteria, S. aureus and S. epidermidis are most commonly found on cardiovascular devices (Otto, 2008. Staphylococcal biofilms. Curr. Top. Microbiol. Immunol. 322:207-228; Otto, M. 2009. Med. Res. Rev. 1-22). It was estimated that S. aureus and S. epidermidis caused about 40-50% of prosthetic heart valve infections, and 50-70% catheter biofilm infections (Agarwal et al., FEMS Immunol. Med. Microbiol. 58:147-160). 250,000-500,000 primary blood stream infections resulted from the 150 million intravascular devices implanted in the USA annually. Each episode of these infections can increase health care cost by $4,000 to $56,000 (Maki et al., 2006. Mayo Clin. Proc. 81:1159-1171; Uckay et al., 2009. Ann. Med. 41:109-119). Approximately 87% of blood stream infections were caused by staphylococci (Agarwal et al., 2010; supra). Taken together, S. aureus and S. epidermidis in biofilm exert a staggering burden on the healthcare system.
Staphylococcus aureus is a major human pathogen, and it is estimated that approximately 30% of humans are asymptomatic nasal carriers (Chambers and DeLeo 2009. Nat. Rev. Microbiol. 7:629-641). S. aureus causes skin, soft tissue, respiratory, bone, joint and endovascular diseases. Life threatening cases caused by S. aureus include bacteremia, endocarditis, sepsis and toxic shock syndrome (Lowy 1998. N. Engl. J. Med. 339:520-532). Antibiotic resistance in S. aureus is increasingly becoming an urgent medical problem. The methicillin resistance in S. aureus is approaching epidemic level (Chambers and DeLeo, supra; Grundmann et al., 2006. Lancet 368:874-885). It was estimated that 94,360 invasive MRSA infections occurred in the US in 2005, and these infections were associated with death in 18,650 cases (Klevens et al., 2007. JAMA 298:1763-1771). Although S. epidermidis is part of the normal human epithelial bacterial flora, it can cause infection when skin or mucous membrane is injured. Biofilm formation on implanted indwelling medical devices is the major manifestation of S. epidermidis pathogenesis (Otto et al., 2008; supra).
Biofilm-associated bacteria are particularly resistant to antibiotic treatment compared to planktonic organisms, probably due to the unique structure of biofilm that prevents antibiotics from reaching the bacteria, or the altered microenvironment within the biofilm that could inactivate antibiotics (Otto et al., 2008; supra). Furthermore, antibiotics mainly target active cell processes, leading to limited efficacy against bacteria in biofilm which are different from planktonic bacteria physiologically. Depletion of nutrition and accumulation of waste within biofilm could induce bacteria into a slow-growing or starved state resistant to antibiotics. Additionally, some bacteria may adopt a distinct biofilm phenotype in response to growing on surfaces which also decreases their sensitivity to antibiotics (Otto et al., 2008; supra; Costerton et al., 1999. Science 284:1318-1322; Fux et al., 2005. Trends Microbiol. 13:34-40; Stewart et al., 2001. Lancet 358:135-138)
In addition to the difficulty of treating biofilm with conventional antibiotic therapy, treating biofilm is further complicated by the rising antibiotic resistance among staphylococcus. Antibiotics target a small set of proteins essential for bacterial survival, such as cell wall formation or synthesis of bacterial DNA, RNA, lipid and protein. As a result, antibiotic resistant strains have been favored by selective pressure (Martinez and Baquero, 2002. Clin. Microbiol. Rev. 15:647-679). Antibiotic resistance in major human pathogens has become a serious public health burden.
Collectively, these factors indicate that novel therapeutic strategies beyond treatment with conventional bactericidal antibiotics are needed to address the morbidity and mortality resulting from biofilm formation.